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New Paradigm for Addressing Joint Health Through Osteoinduction

December 21, 2018

New Paradigm for Addressing Joint Health Through Osteoinduction

A joint or articulation is the area where two adjacent bones are strongly anchored to each other by cartilage or fibrous connective tissue in order to form a connection. There are two classes of joints: functional and structural. Functional joints may be immoveable/fixed (synarthroses joints), partially moveable (amphiarthroses joints), or freely moveable (diarthroses joints). Structural joints include fibrous (fixed) joints in which fibrous connective tissue holds the bones together; cartilaginous (partially moveable) joints in which cartilage connect the bones; and synovial (freely moving) joints. The bones which form a synovial joint are connect by an articular capsule that is comprised of a synovial membrane, articular cartilage, and a joint cavity that is filled with synovial fluid. The joints are further classified into types.

There are three types of fibrous joints:

  • Sutures (e.g., joint between the cranial bones and the skull)
  • Gomphoses (e.g., tooth socket)
  • Syndesmoses (e.g., joint between the fibula and tibia)

There are two types of cartilaginous joints:

  • Symphyses (e.g., intervertebral disc)
  • Synchondroses (e.g., vertebrae)

There are six types of synovial joints:

  • Pivot (e.g., neck)
  • Ball and socket (e.g., shoulders, hips)
  • Gliding (e.g., wrist)
  • Hinge (e.g., fingers, toes)
  • Planar (e.g., ankle)
  • Saddle (e.g., thumb)

Although each of the joints are structured somewhat differently and have distinct functions, tissue that forms the joints are of the same origin. More specifically, mesenchymal stem cells (MSCs) differentiate into multiple cell lineages which include chondrocytes and fibroblasts, among others, and it is the differentiation of these cells that leads to the formation of almost all types of connective tissue such as cartilage, interstitial fibrous tissue, and more dense tissue (e.g., tendons, ligaments). However, MSCs also facilitate the healing of dysfunctional tissue. Indeed, the chondrogenic differentiation of MSCs plays a significant role in cartilage regeneration. In addition, research shows that chondrogenic stimulants such as bone morphogenetic proteins (BMPs), especially BMP-6, increases cartilage matrix deposition. Furthermore, the integration sites of tendons or ligaments with the bone contains specialized tissue called enthesis, which is comprised of fibrocartilaginous tissue, and BMP signaling has been shown to influence fibrocartilaginous growth in rotator cuff repair. BMP-7, in particular, has demonstrated the ability to positively affect tendon-bone integration and healing.


Furthermore, once differentiation occurs, the underlying matrix can begin to be remolded and repaired. In an in vitro model utilizing human articular (point of bone to bone contact) chrondrocytes from healthy and non-healthy tissue, BMP-6 was administered. The key findings from the study were that BMP-6 stimulated growth and repair of joint tissue in both healthy and non-healthy tissue. BMP-6 increased biosynthesis of proteoglycans, thereby suggesting a homeostatic role in maintaining the integrity of adult cartilage. Chondrocytes facilitate the development and repair of the extracellular matrix (ECM) of cartilage by synthesizing matrix components such as glycosaminoglycan side chains and proteoglycans, and then secreting them into the ECM. Therefore, these results demonstrate that BMP signaling has the ability to initiate the repair and strengthen the underlying architecture of numerous tissue types within the joints.This entire process is initiated by the activation of SMADs 1, 5 and 8. In particular, the BMP-activated type I receptor phosphorylates Smad-1, -5, and -8, which leads to the formation of heteromeric complexes with Smad-4. The final complex is translocated into the nucleus where it functions as a transcription factor that induces the expression of BMP-responsive genes. Accordingly, activated SMAD complexes induce MSC DNA, thereby propagating the differentiation of MSCs into chondrocytes. Accordingly, research indicates that chondrocytes regulate the development of the extracellular matrix (ECM) of cartilage. The generation of new cartilage tissue dissipates stress between the soft tissue and bone. This is key in maintaining the mechanical functions of the joint, which over time can deteriorate and cause pain and loss of normal function.

A similar study also showed that the expression of BMP-4 and BMP-5 was significantly decreased in the synovial tissue in comparison to normal donors (NDs). There was also decreased BMP-4 and BMP-5 expression in the synovial tissue of participants with OA in comparison to NDs. These findings indicate that BMP plays a specific role in joint homeostasis that is disrupted by inflammatory signaling. The results also suggest that BMP supplementation has restorative properties on the joints.


In addition to maintaining the proper cellular groundwork for repair, BMP activation can have a rapid response on pain signaling in the joint due to interleukin regulation/feedback. The proliferation of inflammatory cytokines, such as interleukin IL-1 and IL-6, within the joint space can have detrimental effects on joint tissue. IL-1, in particular, activates matrix metalloproteinases (MMPs) and the NF-Kappa B transcription factor. Cyplexinol® is the only orally available BMP-Complex providing the active signaling peptides.

Commonly recommended joint health supplements such as MSM, SAMe, or glucosamine/chondroitin have an indirect effect on inflammatory balance and joint comfort, but they do not stimulate de novo formation of cartilage.* MSM maintains healthy inflammatory balance through free radical scavenging activity that is believed to facilitate the removal of inflammatory metabolic waste.* SAMe has provided joint comfort support for some individuals, which reflects improved joint mobility.* Glucosamine is naturally found in cartilage and other

connective tissues, while chondroitin promotes the retention of water in cartilage, thereby providing protective cushioning for the joints.*Therefore, MSM, SAMe, or glucosamine/chondroitin may help improve joint mobility and functionality, but ultimately only act as building blocks that chondrocytes can absorb and use to create proteins such as proteoglycans.* Products containing these ingredients do not help support the differentiation of MSCs into chondrocytes.*

Similarly, newer agents such as egg shell membrane (ESM), hyaluronic acid, and UC-II (undenatured collagen) have shown some clinical benefit, but do not possess the ability to help support cartilage growth.* More specifically, ESM is a rich source of collagen, hyaluronic acid, amino acids, glucosamine, and chondroitin, but ESM has the same function as each of the individual supplements above* Once again, ESM would only provide cartilage building blocks for chondrocytes.* Hyaluronic acid, which is also a component of ESM, only cushions and lubricates joints.* Furthermore, collagen preparations (e.g., UC-II) are fully hydrolyzed products that degrade the BMPs and other growth factors, leaving collagen peptides that solely consist of purified collagen that does not contain bone or cartilage stimulating proteins.*

Therefore, Cyplexinol® is the only BMP-Complex that not only supports a healthy immune response, but differentiates MSCs into chondrocytes which grow de novo cartilage tissue.* This makes it the only osteoinductive complex which can support the stimulation and formation of cartilage.* In particular, clinical research has demonstrated the efficacy of Cyplexinol® in addressing both bone and joint health, thereby offering all individuals a new and innovative option in supporting bone and joint health.*

 

References

  1. Scott AS, Fong E. Boston, MA: Cengage Learning, 2013.
  2. Marion NW, Mao JJ. Methods Enzymol. 2006; 420:339-61.
  3. Sekiya I, Colter DC, Prockop DJ. Biochem Biophys Res Commun. 2001 Jun 8; 284(2):411-8.
  4. Lee KW, Lee JS, Kim YS et al. J Biomed Mater Res B Appl Biomater. 2016.
  5. Schwarting T, Lechler P, Struewer J, et al. 2015; 10(2): e0116833.
  6. Miyazawa K, Shinozaki M, Hara T, Furuya T, Miyazono K. Genes Cells. 2002 Dec; 7(12):1191-204.
  7. Sophia Fox AJ, Bedi A, Rodeo SA. Sports Health. 2009 Nov;1(6):461-8.
  8. Shahab-Osterloh S, Witte F, Hoffmann A, et al. Stem Cells. 2010 Sep;28(9):1590-601.
  9. Bobacz K, Gruber R, Soleiman A, Erlacher L, Smolen JS, Graninger WB. Arthritis Rheum. 2003 Sep;48(9):2501-8.
  10. Sophia Fox AJ, Bedi A, Rodeo SA. Sports Health. 2009 Nov;1(6):461-8.
  11. Bramlage CP, Häupl T, Kaps C, Ungethüm U, Krenn V, Pruss A, Müller GA, Strutz F, Burmester GR. Arthritis Res Ther. 2006;8(3): R58

 

Dr. BucciDr. Bucci holds a PhD in Biomedical Sciences (Biochemistry and Cell Biology), from the University of Texas Health Science Center. He previously was the Research Director for Biotics Research Corp. and then served as the first Director of Science and Quality at SpectraCell Laboratories Inc. Dr. Bucci was Vice President, Research for Weider/Schiff Nutrition for over 17 years, and Research & Scientific Affairs Specialist for Schiff Nutrition after its acquisition by Reckitt Benckiser in 2013. 





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